Guo, Qianqian

Furuta, Kunimaro

Islam, Shahidul

Caporarello, Nunzia

Kostallari, Enis

Dielis, Kobe

Tschumperlin, Daniel J

Hirsova, Petra

Ibrahim, Samar H

2022-08-25

<p><b>Background:</b> During liver injury, liver sinusoidal endothelial cells (LSECs) dysfunction and capillarization promote liver fibrosis. We have previously reported that the LSEC vascular cell adhesion molecule 1 (VCAM1) plays a key role in liver inflammation in nonalcoholic steatohepatitis (NASH) and we now aim to uncover its role in LSEC capillarization and liver fibrosis.</p> <p><b>Methods:</b> Wild-type C57BL/6J mice were fed either chow or high fat, fructose and cholesterol diet to induce NASH and treated with either anti-VCAM1 neutralizing antibody or control isotype antibody. Inducible endothelial cell-specific Vcam1 deleted mice (<i>Vcam1^Δend</i>) and control mice (<i>Vcam1^fl/fl</i>) were fed choline-deficient high-fat diet (CD-HFD) to induce NASH or injected with carbon tetrachloride to induce liver fibrosis. LSECs isolated from <i>Vcam1^fl/fl</i> or <i>Vcam1^Δend</i> and hepatic stellate cells (HSCs) isolated from wild-type mice were cocultured in a 3-D system or a μ-Slide 2 well co-culture system.</p> <p><b>Results:</b> Immunostaining for Lyve1 (marker of differentiated LSECs) was reduced in <i>Vcam1^fl/fl</i> mice and restored in <i>Vcam1^Δend</i> mice in both NASH and liver fibrosis models. Co-immunostaining showed increased α-smooth muscle actin in the livers of <i>Vcam1^fl/fl</i> mice in areas lacking Lyve1. Furthermore, scanning electron microscopy showed reduced LSEC fenestrae in the <i>Vcam1^fl/fl</i> mice but not <i>Vcam1^Δend</i> mice in both injury models, suggesting that VCAM1 promotes LSEC capillarization during liver injury. HSCs profibrogenic markers were reduced when cocultured with LSECs from CD-HFD fed <i>Vcam1^Δend</i> mice compared to <i>Vcam1^fl/fl</i> mice. Furthermore, recombinant VCAM1 activated the Yes-associated protein 1 pathway and induced a fibrogenic phenotype in HSCs <i>in vitro</i>, supporting the profibrogenic role of LSEC VCAM1.</p> <p><b>Conclusion:</b> VCAM1 is not just a scaffold for leukocyte adhesion during liver injury, but also a modulator of LSEC capillarization and liver fibrosis.</p>

Frontiers in Immunology, v.13, p. 1-15

1664-3224

https://hdl.handle.net/1959.11/70418

en

Frontiers Research Foundation

Attribution 4.0 International

Liver sinusoidal endothelial cell expressed vascular cell adhesion molecule 1 promotes liver fibrosis

Journal Article

Publication